An LC-MS/MS Assay for Simultaneous Quantitation of Docetaxel and its Prodrug-Conjugate for Pharmacokinetic Studies of PRINT-Lipidized-Docetaxel Nanoparticles in Mice

摘要

LC-MS/MS conditions were optimized to enable separation of docetaxel and each prodrug conjugate (Figure 1). The assay performance variables (Table 1) for the validated assays proved suitable for application to PK studies of NP formulations of the prodrugs. Ex vivo stability of the prodrug conjugates in plasma (Figure 2) shows that conversion occurs faster for the C2-dimethyl-Si-DTXL conjugate than the C8-dimethyl-Si-DTXL conjugate (Table 3). Conversion of the C8-diisopropyl-Si-DTXL conjugate was not observed (Figure 2), potentially due to steric hindrance by the bulky group at the silyl-ether linkage. Docetaxel exposure was greater for all PRINT formulations compared to Taxotere(small molecule drug) (Figure 3, Table 2). As predicted by the ex vivo stability studies, the extent of conversion in plasma was greater for the C2- as compared to the C8-dimethyl-Si-DTXL conjugate, whereas no conversion was detected beyond 5 minutes for the C8-diisopropyl-Si-DTXL conjugate. (Figure 3). Ongoing and future studies will evaluate the efficacy and PK of the NP formulation of C2-dimethyl-Si-DTXL conjugate relative to free drug and non-lipidized PRINT-DTXL NPs.